In the field of X-ray radiography using an iodine compound, for example, X-ray angiography, a technique is available which comprises administration of a water-soluble iodine-containing contrast medium for visualization of vascular flows, and detection of lesions at which the flows are obstructed. However, in the aforementioned method, the iodine-containing contrast medium is present in the vascular flows to detect changes of vascular flows inside the vessels, and the method has difficulty in distinguishing the lesions from normal tissues as compared to a method wherein an iodine-containing contrast medium is present in cells consisting a lesion. For this reason, by the above method, only a lesion where constriction progresses 50% or more can be detected, and it is difficult to detect a lesion before the onset of attack of an ischemic disease.
Separately, attempts have also been reported in which a hydrophobic iodine-containing contrast medium or a hydrophilic contrast medium is formulated for selective accumulation in a target lesion (International Patent Publications WO95/19186, WO95/21631, WO89/00812, British Patent No. 867650, WO96/00089, WO94/19025, WO96/40615, WO95/2295, WO98/41239, WO98/23297, WO99/02193, WO97/06132, U.S. Pat. Nos. 4,192,859, 4,567,034, 4,925,649, Pharm. Res., 6 (12), 1011 (1989); Pharm. Res., 16 (3), 420 (1999); J. Pharm. Sci., 72 (8), 898 (1983); Invest. Radiol., 18 (3), 275 (1983)). For example, Pharm. Res., 6 (12), 1011 (1989) discloses that injection of an oil-particle dispersion of cholesteryl iopanoate as a hydrophobic compound allows accumulation of the iodine compound in arteriosclerotic lesions of experimental animals. Further, Pharm. Res., 16 (3), 420 (1999) discloses that administration of cholesteryl iopanoate after being taken up into acetyl-LDL allows accumulation of the iodine compound in arteriosclerotic lesions of experimental animals.
J. Pharm. Sci. 72 (8), 898 (1983) discloses examples of X-ray hepatography and splenography by injection of an oil-particle dispersion of cholesteryl iopanoate. U.S. Pat. No. 4,567,034 discloses a method of selective hepatography or splenography utilizing liposomes encapsulating an ester of diatrizoic acid. International Patent Publications WO96/28414 and WO96/00089 disclose contrast media for imaging vascular pools or lymphatic systems. However, the methods using these formulations are not satisfactory in efficiency and selectivity for a purpose of selective contrast of vascular diseases, and no example is reported in which vascular diseases are imaged by utilizing X-ray irradiation.
International Publication WO01/93918 discloses an example of radiography of arteriosclerotic lesions, wherein a hydrophobic and hydrolysis-resistant radioactive iodine-containing contrast medium is formulated into a microemulsion or allowed to be taken up into acetyl-LDL and then administered to experimental animals. Further, it is also reported that the aforementioned cholesteryl iopanoate is not degraded in living bodies and accumulated in organs in vivo, in particular, livers [J. Med. Chem., 25, 1500 (1982)]. These properties of the compounds indicate that the compounds remain in living bodies for a prolonged period of time, and the properties are not favorable when diagnostic use such as X-ray contrast media is desired.
From a viewpoint of intended use of chemical compounds, methods have been reported in which a triglyceride compound comprising an alkylcarboxylic acid formed by two of 3-amino-2,4,6-triiodophenyl groups and a saturated/unsaturated fatty acid is formulated as an oil particle dispersion (lipid emulsion) or a Tween 20 dispersion and used for the purpose of hepatography or imaging of blood-pool (Radiology, 216 (3) 865 (2000); Invest. Radiol., 35 (3), 158 (2000); International Patent Publication WO98/46275; J. Pharm. Sci., 85 (9), 908 (1996); Pharm. Res., 13 (6), 875 (1996); International Patent Publication WO95/31181; J. Med. Chem., 38 (4), 636 (1995); Invest. Radiol., 29 (SUPPL. 2), S284 (1994); International Patent Publication WO94/19025; U.S. Pat. No. 4,873,075; Appl. Radiol. Isot., 37 (8), 907 (1986); J. Med. Chem., 29 (12), 2457 (1986)). Further, U.S. Pat. No. 4,873,075 and J. Med. Chem., 29 (12), 2457 (1986) mentioned above describe diacyl-1,3-glyceride compounds comprising an alkylcarboxylic acid containing two of 3-amino-2,4,6-triiodophenyl groups and oxidized compounds thereof. However, a use thereof other than as synthetic intermediates is not described. Moreover, the 2-position of the glycerin moiety is unsubstituted, and the compounds have no structurally characteristic functional group.
Phosphoric acid esters of diacylglyceride compounds comprising a saturated/unsaturated long chain fatty acid, in particular, those compound of which 1-position is esterified with phosphoric acid, are found as a membrane component of organisms, and therefore, various derivatives thereof have been known. However, most of these compounds are phosphoric acid ester compounds comprising an unsubstituted saturated/unsaturated fatty acid. In particular, compounds having an iodophenyl group in the structures are described in J. Amer. Chem. Soc., 117 (11), 3084 (1995); J. Org. Chem., 61 (1), 192 (1996); Eur. J. Org. Chem., 10, 2563 (1999); Tetrahedron Lett., 41 (35), 6737 (2000) and the like. However, these compounds have only one monoiodophenyl group in their structures. Although Tetrahedron Lett., 27 (3), 271 (1986) describes compounds having tyroxine, the bonding position of the tyroxine moiety is not in the aliphatic acid moiety, but at the end of the phosphoric acid ester moiety, and therefore their structural characteristic is totally different from that of the compounds of the present invention.